rs116719245

chr2-219281737-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006736.6(DNAJB2):c.195C>T(p.Tyr65=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,613,964 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: DNAJB2 NM_006736.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.799

Genes affected

DNAJB2 (HGNC:5228): (DnaJ heat shock protein family (Hsp40) member B2) This gene is almost exclusively expressed in the brain, mainly in the neuronal layers. It encodes a protein that shows sequence similarity to bacterial DnaJ protein and the yeast homologs. In bacteria, this protein is implicated in protein folding and protein complex dissociation. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-219281737-C-T is Benign according to our data. Variant chr2-219281737-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219281737-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.799 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00114 (174/152218) while in subpopulation NFE AF= 0.00232 (158/68016). AF 95% confidence interval is 0.00203. There are 2 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJB2	NM_006736.6	c.195C>T	p.Tyr65=	synonymous_variant	4/9	ENST00000336576.10
DNAJB2	NM_001039550.2	c.195C>T	p.Tyr65=	synonymous_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB2	ENST00000336576.10	c.195C>T	p.Tyr65=	synonymous_variant	4/9	1	NM_006736.6

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152100 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000907 AC: 228 AN: 251256 Hom.: 0 AF XY: 0.000891 AC XY: 121 AN XY: 135798

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00155 AC: 2259 AN: 1461746 Hom.: 6 Cov.: 33 AF XY: 0.00150 AC XY: 1092 AN XY: 727166

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152218 Hom.: 2 Cov.: 32 AF XY: 0.000914 AC XY: 68 AN XY: 74416

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00232

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.00109

EpiCase AF: 0.00207

EpiControl AF: 0.00202

ClinVar

Significance: Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DNAJB2: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Neuronopathy, distal hereditary motor, autosomal recessive 5 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 22, 2023	- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DNAJB2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	6.5
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs116719245; hg19: chr2-220146459;